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J. Biol. Chem., Vol. 283, Issue 31, 21315-21324, August 1, 2008

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Antagonistic Effects of the SRp30c Protein and Cryptic 5 ' Splice Sites on the Alternative Splicing of the Apoptotic Regulator Bcl-x^*

Philippe Cloutier, Johanne Toutant, Lulzim Shkreta, Serge Goekjian, Timothée Revil, and Benoit Chabot¹

From the RNA/RNP Group, Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada, and the Department of Biochemistry, Bishop's University, Lennoxville, Québec J1M 1Z7, Canada

Alternative 5 ' splice site selection allows Bcl-x to produce two isoforms with opposite effects on apoptosis. The pro-apoptotic Bcl-x_S variant is up-regulated by ceramide and down-regulated by protein kinase C through specific cis-acting exonic elements, one of which is bound by SAP155. Splicing to the Bcl-x_S 5 ' splice site is also enforced by heterogeneous nuclear ribonucleoprotein (hnRNP) F/H proteins and by Sam68 in cooperation with hnRNP A1. Here, we have characterized exon elements that influence splicing to the 5 ' splice site of the anti-apoptotic Bcl-x_L isoform. Within a 86-nucleotide region (B3) located immediately upstream of the Bcl-x_L donor site we have identified two elements (ML2 and AM2) that stimulate splicing to the Bcl-x_L 5 ' splice site. SRp30c binds to these elements and can shift splicing to the 5 ' splice site of Bcl-x_L in an ML2/AM2-dependent manner in vitro and in vivo. The B3 region also contains an element that represses the use of Bcl-x_L. This element is bound by U1 small nuclear ribonucleoprotein and contains two 5 ' splice sites that can be used when the Bcl-x_L 5 ' splice site is mutated or the ML2/AM2 elements are deleted. Conversely, mutating the cryptic 5 ' splice sites stimulates splicing to the Bcl-x_L site. Thus, SRp30c stimulates splicing to the downstream 5 ' splice site of Bcl-x_L, thereby attenuating the repressive effect of upstream U1 snRNP binding sites.

Received for publication, January 14, 2008 , and in revised form, June 2, 2008.

^* This study was supported by the Canadian Institute of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ Holds a Canada Research Chair in Functional Genomics. To whom correspondence should be addressed. Tel.: 819-564-5321; Fax: 819-564-5392; E-mail: Benoit.Chabot{at}USherbrooke.ca.

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